The etiology of the pruritus of cholestasis is unknown and its treatment unsatisfactory. The pruritus of cholestasis has a negative impact on the quality of life of patients and it can be so severe that it alone can be an indication for liver transplantation in children and adults, even in the face of good hepatic function. Accordingly, the provision of satisfactory treatment for this symptom is needed. The spontaneous disappearance of pruritus in patients with cholestasis heralds liver failure. In addition, replacement of the diseased liver in a patient who has cholestasis and pruritus is followed by the cessation of this symptom. These two clinical observations suggest that a certain degree of hepatic function is necessary for the pruritus of cholestasis to be perceived and that the cholestatic liver participates in the production of the pruritogenic substance. The measurement of substances that are found in plasma as a method of research in the field of pruritus has not led to progress in the elucidation of the pathogenesis of the pruritus of cholestasis. Because pruritus is a perception, it cannot be objectively quantitated. Recently however, clinical studies that have incorporated quantitative methodology to measure scratching behavior, have suggested that the pruritus of cholestasis is in part, mediated by endogenous opioids. In these studies, the administration of opiate antagonist drugs ameliorated the perception of pruritus and the scratching activity index, which is the behavioral manifestation of the pruritus of cholestasis. An animal model of scratching behavior in animals has been developed recently. The use of animal models in the study of the pruritus of cholestasis offers the opportunity to discover the substance, or group of substances, which mediate this form of pruritus. The aim of this proposal is to adapt an assay of centrally mediated scratching behavior in rats. This assay will be used to study the scratch-inducing capacity of cholestatic extracts from patients with liver disease and itch and from rats after their central administration. The long term objective of these studies is to identify that substances that mediate the pruritus of cholestasis and to develop effective specific therapies for this complication of liver disease.